X-91876958-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_032968.5(PCDH11X):c.718A>T(p.Thr240Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,208,038 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 99 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 5 hem., cov: 20)
  • Exomes 𝑓: 0.00025 (0 hom. 94 hem.)
• Consequence: PCDH11X NM_032968.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.02

Genes affected

PCDH11X (HGNC:8656): (protocadherin 11 X-linked) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The encoded protein consists of an extracellular domain containing 7 cadherin repeats, a transmembrane domain and a cytoplasmic tail that differs from those of the classical cadherins. The gene is located in a major X/Y block of homology and its Y homolog, despite divergence leading to coding region changes, is the most closely related cadherin family member. The protein is thought to play a fundamental role in cell-cell recognition essential for the segmental development and function of the central nervous system. Disruption of this gene may be associated with developmental dyslexia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13381535).
• BP6: Variant X-91876958-A-T is Benign according to our data. Variant chrX-91876958-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1087134.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH11X	NM_032968.5	c.718A>T	p.Thr240Ser	missense_variant	6/11	ENST00000682573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH11X	ENST00000682573.1	c.718A>T	p.Thr240Ser	missense_variant	6/11		NM_032968.5	P4

Frequencies

GnomAD3 genomes AF: 0.000300 AC: 33 AN: 109904 Hom.: 0 Cov.: 20 AF XY: 0.000156 AC XY: 5 AN XY: 32084

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000494

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000352

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000473

Gnomad OTH AF: 0.000674

GnomAD3 exomes AF: 0.000229 AC: 42 AN: 183292 Hom.: 0 AF XY: 0.000162 AC XY: 11 AN XY: 67862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000500

Gnomad NFE exome AF: 0.000367

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000247 AC: 271 AN: 1098091 Hom.: 0 Cov.: 31 AF XY: 0.000259 AC XY: 94 AN XY: 363565

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.000280

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000300 AC: 33 AN: 109947 Hom.: 0 Cov.: 20 AF XY: 0.000156 AC XY: 5 AN XY: 32137

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000493

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000352

Gnomad4 NFE AF: 0.000473

Gnomad4 OTH AF: 0.000665

Alfa AF: 0.000218 Hom.: 1

Bravo AF: 0.000287

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.718A>T (p.T240S) alteration is located in exon 2 (coding exon 2) of the PCDH11X gene. This alteration results from a A to T substitution at nucleotide position 718, causing the threonine (T) at amino acid position 240 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	6.4
Dann	Benign	0.77
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.52	T;T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;L;L;L
MutationTaster	Benign	0.92	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.69	T;T;T;T;T;T
Sift4G	Benign	0.70	T;T;T;T;T;T
Polyphen		0.0090	B;B;B;B;B;B
Vest4		0.098
MutPred		0.52		Gain of disorder (P = 0.0553);Gain of disorder (P = 0.0553);Gain of disorder (P = 0.0553);Gain of disorder (P = 0.0553);Gain of disorder (P = 0.0553);Gain of disorder (P = 0.0553);
MVP		0.72
MPC		1.0
ClinPred		0.040	T
GERP RS		-0.33
Varity_R		0.074
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140764964; hg19: chrX-91131957;